G Model BCP-10654; No. of Pages 11 Biochemical Pharmacology xxx (2010) xxx–xxx Contents lists available at ScienceDirect Biochemical Pharmacology journal homepage: www.elsevier.com/locate/biochempharm Review Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer Hareesh B. Nair a,*, Bokyung Sung b, Vivek R. Yadav b, Ramaswamy Kannappan b, Madan M. Chaturvedi b,1, Bharat B. Aggarwal b,** a Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA b Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA ARTICLE INFO ABSTRACT Article history: Extensive research within the last two decades has revealed that most chronic illnesses, including Received 17 May 2010 cancer, diabetes, and cardiovascular and pulmonary diseases, are mediated through chronic Accepted 13 July 2010 inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and even Available online xxx treat various chronic diseases, including cancer. Various nutraceuticals from fruits, vegetables, vitamins, spices, legumes, and traditional Chinese and Ayurvedic medicine have been shown to safely suppress Keywords: proinflammatory pathways; however, their low bioavailability in vivo limits their use in preventing and Inflammation treating cancer. We describe here the potential of nanotechnology to fill this gap. Several nutraceuticals, Diabetes including curcumin, green tea polyphenols, coenzyme Q, quercetin, thymoquinone and others, have Cancer NF-kB been packaged as nanoparticles and proven to be useful in ‘‘nanochemoprevention’’ and ‘‘nano- Curcumin chemotherapy’’. Nutraceuticals ß 2010 Elsevier Inc. All rights reserved. Nanotechnology Contents 1. Introduction . 000 2. Inflammation, chronic diseases and cancer . 000 3. Antiinflammatory nutraceuticals. 000 4. Nanotechnology . 000 5. Formulation technologies . 000 5.1. Nanoprecipitation . 000 5.2. Nanoemulsion techniques . 000 5.3. Reverse-phase evaporation. 000 6. Role of nanotechnology for nutraceuticals . 000 7. In vivo pharmacokinetics . 000 8. Conclusion...................................................................................................... 000 Acknowledgements . 000 References...................................................................................................... 000 1. Introduction The natural products are valuable sources of bioactive compounds [1], and have been considered the single most * Corresponding author. Tel.: +1 210 567 5028; fax: +1 210 576 4958. successful discovery of modern medicine [2]. In recent years, ** Corresponding author. Tel.: +1 713 794 1817; fax: +1 713 745 6339. natural dietary agents have drawn a great deal of attention both E-mail addresses: [email protected] (H.B. Nair), [email protected] (B.B. Aggarwal). from researchers and the general public because of their potential 1 Present address: Department of Zoology, University of Delhi, Delhi 110007, ability to suppress cancers as well as reduce the risk of cancer India. development [3]. However, a large number of natural products 0006-2952/$ – see front matter ß 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2010.07.021 Please cite this article in press as: Nair HB, et al. Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer. Biochem Pharmacol (2010), doi:10.1016/j.bcp.2010.07.021 G Model BCP-10654; No. of Pages 11 2 H.B. Nair et al. / Biochemical Pharmacology xxx (2010) xxx–xxx have never been replicated by synthetic medicinal chemistry, virus nanoparticles, and magnetic nanoparticles [11] (Fig. 1). Some which illustrates the importance of drug discovery to identify of the commonly used methods to characterize the nanoparticles active compounds and define novel pharmacophores [4]. Also are depicted in Fig. 2. The most noticeable nanotechnologic because of their low solubility, many phytochemicals are poorly applications in medicine have been related to oncology [12,13].In absorbed by human body, thus one of the most important and this review, we discuss the recent advances made in approaches for interesting applications for encapsulation of phytochemicals is to targeting anticancer bioactive natural products in both basic enhance the bioavailability of phytochemicals by changing the research and clinical trials. pharmacokinetics and biodistribution [5]. In the past decade, tremendous advancement has been made 2. Inflammation, chronic diseases and cancer toward making nanoparticle-based therapeutic products and formulations commercially available. A 2006 European Technologi- A growing body of evidence suggests that many neoplasms are cal Observatory survey showed that more than 150 pharmaceutical initiated by infections [14]. Some recent reviews have discussed companies were developing nanoscale therapeutics [6]. The idea of intimate connection between inflammation and cancer [15–17]. controlled drug delivery has been shown to improve the therapeutic Inflammation is known to contribute to physiological and index of drugs by increasing their localization to specific tissues, pathological processes such as wound healing and infection by organs, or cells [7,8]. This approach tends to decrease potential side the activation and directed migration of leukocytes from the effects by leaving the normal sensitive cells unharmed. Contempo- venous system to sites of damage [14]. Inflammation functions at rary systemically administered chemotherapeutic agents are all three stages of tumor development: initiation, progression, and extremely toxic to cancer cells, but can also harm normal cells metastasis. Tumor cells produce various cytokines and chemokines leading to serious side effects [9]. Controlled drug delivery systems that attract leukocytes. The inflammatory component of a administer the required amount of the drug to the target site and developing neoplasm may include a diverse leukocyte population prevent it from circulating until its half-life finishes. The career that includes neutrophils, dendritic cells, macrophages, eosino- system associated with site-specific drug delivery can be modulated phils, and mast cells [18]. It is believed that tumor-associated for better pharmacokinetics and drug bioavailability [5].Morethan macrophages are a significant component of inflammatory half of the chemotherapeutic agents currently being administered infiltrates in neoplastic tissues and are derived from monocytes either are plant derived or semisynthetic in nature. The inevitable that are recruited largely by monocyte chemotactic protein (MCP) share of botanicals, therefore, in the development of modern chemokines. The proinflammatory cytokines, including tumor chemotherapeutics is beyond doubt. Several different classes of necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6), induce active natural products have been documented. direct effects on stromal and neoplastic cells in addition to their According to the National Nanotechnology Initiative (NNI; roles in regulating leukocyte recruitment. The direct evidence for http://www.nano.gov) nanotechnologic structures should be only the association of chronic inflammation with malignant diseases is 1–100 nm in at least one dimension. This size requirement can be in colon carcinogenesis in individuals with inflammatory bowel achieved through various rational designs, including top-down diseases [19,20]. The emerging concept in clinical trials reveals that and bottom-up approaches. Nanocarriers have the potential to inflammation is a potential therapeutic target in cancer treatment modify modern drugs by increasing their efficacy, stability, and and nonsteroidal antiinflammatory drugs are thereby potentially solubility; decreasing their toxicity; and sustaining their release useful as adjuvant therapy [21]. [10]. Nanoparticulate drug delivery systems using liposomes and Inflammation also plays a key role in the physiology of arthritis, biodegradable polymers have attracted increasing attention in diabetes, heart disease, irritable bowel syndrome, Alzheimer’s recent years. In addition to liposomes and biodegradable polymers, disease, Parkinson’s disease, and many other illnesses. In Type I the most common materials for nanocarriers include dendrimers, diabetes, the immune system attacks the cells that make insulin. Fig. 1. Different types of nanoparticles. Diagrammatic representation of some commonly nanocarriers used for the delivery of neutraceuticals. These include dendrimers, virus nanoparticles, and magnetic nanoparticles. Please cite this article in press as: Nair HB, et al. Delivery of antiinflammatory nutraceuticals by nanoparticles for the prevention and treatment of cancer. Biochem Pharmacol (2010), doi:10.1016/j.bcp.2010.07.021 G Model BCP-10654; No. of Pages 11 H.B. Nair et al. / Biochemical Pharmacology xxx (2010) xxx–xxx 3 Fig. 2. Physical characterization of the nanoparticles. Some of the commonly used methods to characterize the nanoparticles are depicted in the figure. (A) Scanning electron microscopy (SEM) image of nanoparticles; (B) transmission electron microscopy (TEM) image; (C) SEM image of nanoparticles after mechanical extrusion; (D) determination of size distribution of nanoparticles by use of dynamic light scattering (DLS). Children who have allergies are less likely to develop Type I its incorporation into